TMAO和尿素对淀粉样七肽（<sup>23</sup> FGAILSS <sup>29</sup>）二聚体和四聚体的影响。,ACS Omega

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TMAO和尿素对淀粉样七肽（²³ FGAILSS ²⁹）二聚体和四聚体的影响。
ACS Omega ( IF 3.7 ) Pub Date : 2020-09-29 , DOI: 10.1021/acsomega.0c01031
Ashma Khan ₁ , Shahid M. Nayeem ₁

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人胰岛淀粉样多肽（hIAPP）（1-37）是一种固有的无序蛋白，通过胰腺中的β细胞与胰岛素一起释放。在某些环境条件下，hIAPP可能聚集，从而导致β细胞死亡。hIAPP蛋白的FGAILSS（23–29）残留物形成β折叠，在2型糖尿病（T2D）患者中可能是有毒物质。已使用全原子分子动力学（MD）模拟来分析两种不同类型的渗透液三甲胺N-氧化物（TMAO）和尿素对两种和四种FGAILSS七肽的影响。TMAO导致单个肽趋向于具有更高回转半径的延伸构象，并随着其浓度的增加而促进反平行β-折叠的形成。但是，尿素除4以外大部分都显示单个肽的紧密性。在四聚体的情况下为0 M，但总体上未显示聚集行为。TMAO通过增加其浓度将二聚体和四聚体两者引导至天然状态。而且，二聚体和四聚体在尿素中均表现出不规则的行为。在4.0 M尿素中的四聚体由于形成了反平行的β-折叠而显示出最大程度的天然接触。反平行β-折叠的这种形成有利于肽的聚集。与TM相比，TMAO与肽形成的氢键数量较少，这是因为TMAO的排斥和尿素在肽周围的积累已在第一溶剂化壳（FSS）中发生。主成分分析（PCA）结果表明，对于较小构造盆地的TMAO，在自由能景观（FEL）图中的最小值对于特定构型是均匀的，而在尿素中，二聚体显示最小值，主要用于扩展构象。对于4.0 M尿素浓度，四聚体显示出最小的反平行β-折叠，这表明四聚体的聚集行为，而对于更高浓度，则显示出最小值，具有扩展构象的盆。

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Effect of TMAO and Urea on Dimers and Tetramers of Amyloidogenic Heptapeptides (23FGAILSS29)

Human islet amyloid polypeptide (hIAPP) (1–37) is an intrinsically disordered protein that is released with insulin by β-cells found in the pancreas. Under certain environmental conditions, hIAPP can aggregate, which leads to β-cell death. FGAILSS (23–29) residues of the hIAPP protein form β sheets, which may be toxic species in type 2 diabetes (T2D) patients. All-atom molecular dynamics (MD) simulations have been used to analyze the effect of two distinct types of osmolytes trimethylamine N-oxide (TMAO) and urea on two and four FGAILSS heptapeptides. TMAO leads the individual peptide toward an extended conformation with a higher radius of gyration and favors the formation of antiparallel β-sheets with an increase in its concentration. However, urea mostly shows compaction of individual peptides except at 4.0 M in the case of a tetramer but does not show aggregation behavior as a whole. TMAO leads both the dimer and tetramer toward the native state with an increase in its concentration. Moreover, both the dimer and tetramer show irregular behavior in urea. The tetramer in 4.0 M urea shows the maximum fraction of native contacts due to the formation of antiparallel β-sheets. This formation of antiparallel β-sheets favors the aggregation of peptides. TMAO forms a smaller number of hydrogen bonds with peptides as compared to urea as the exclusion of TMAO and accumulation of urea around the peptides have occurred in the first solvation shell (FSS). Principal component analysis (PCA) results suggest that the minima in the free energy landscape (FEL) plot are homogeneous for a particular conformation in TMAO with smaller basins, while in urea, the dimer shows minima mostly for extended conformations. For a 4.0 M urea concentration, the tetramer shows the minimum for antiparallel β-sheets, which indicates the aggregation behavior of the tetramer, and for a higher concentration, it shows minima with wider basins of extended conformations.

更新日期：2020-10-28

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